More than 1,500,000 individuals in the US are diagnosed with cancer every year. Cachexia (defined as an involuntary weight loss due to adipose tissue and skeletal muscle loss), and anorexia (decreased food intake) are present in up to 80% of these patients, contributing to the decrease in functional performance, quality of life and survival seen in this setting; however, treatments for this condition are lacking. Ghrelin is a novel anabolic hormone that increases energy intake and decreases energy expenditure and inflammation leading to an increase in muscle and fat mass; although, its mechanisms of action in the setting of cancer cachexia are not fully understood. To this date, the only identify receptor for ghrelin is the growth hormone secretagogue receptor 1a (GHSR-1a) and this receptor is not present in muscle or adipose tissue. Recent data has shown that some of ghrelin's effects are GHSR-1a-independent. The objectives of this proposal are to characterize the mechanisms of action of ghrelin and GHSR-1a agonists in muscle and adipose tissue and to establish the extent to which these mechanisms are GHSR-1a-dependent in cancer cachexia. We hypothesize that ghrelin ameliorates cancer cachexia by inducing: 1) GHSR-1a- dependent increases in appetite, GH/IGF-I and downregulation of inflammation, and 2) GHSR-1a-independent decreases in proteolysis by acting directly on muscle cells. We also hypothesize that ghrelin increases lipogenesis and downregulates lipid oxidation and lipolysis in tumor-induced cachexia through GHSR-1a- dependent and independent mechanisms. Our specific aims are: 1) To determine the role of the ghrelin receptor GHSR-1a in mediating the effects of ghrelin in tumor-induced cachexia in rodent muscle. Using our already established in-vivo model (Lewis Lung Carcinoma [LLC]-induced cachexia) in GHSR-1a WT and KO mice, we will determine the role of GHSR-1a activation in modulating muscle mass and strength, inflammation, proteolysis and protein synthesis in this setting. 2) To characterize GHSR-1a-independent mechanisms of action of ghrelin in muscle. Based on our preliminary data showing that the GHSR-1a is not necessary for ghrelin to prevent cisplatin-induced proteolysis in C2C12 cells, and that ghrelin partially prevent LLC-induced cachexia in GHSR-1a KO, we will study these effects in- vivo in our LLC-induced cachexia model and in-vitro in C2C12 cells and 1ry myocyte culture from GHSR-1a KO mice. We will characterize the pathways mediating these GHSR-1a-independent effects of ghrelin and perform experiments to identify the alternate receptor responsible for these effects. 3) To establish the role of GHSR-1a in mediating the effects of ghrelin in adipose tissue. As shown in our cisplatin model, we will study the role of ghrelin in preventing fat atrophy induced by LLC tumor and the relative contribution of lipogenesis, lipolysis and lipid oxidation in this setting. Using our GHSR-1a WT and KO animals we will also establish the role of GHSR-1a in mediating ghrelin's effect in fat in-vivo and in-vitro. The development of therapies for the prevention or treatment of cancer-related fat and muscle wasting is desperately needed because they significantly reduce quality of life in Veterans with cancer. The present proposal will provide insight into ghrelin's mechanisms of action, determine which of these effects are GHSR- 1a-dependent and which are GHSR-1a-independent, characterize these two pathways and identify this novel receptor. Taken together, these experiments will determine the mechanisms mediating ghrelin's protective effects in this setting, addressing a clinical need and filling a void in the literature. Ultimately, these results will allow for better targeting of this pathway and the development of novel therapies for this condition. Other conditions such as chronic obstructive pulmonary disease, heart failure and frailty of the elderly are also associated with muscle and fat loss and will benefit from the advance in knowledge that this proposal will bring.